PGI2 11,15-Ether intermediates

ABSTRACT

The present invention relates to PGI 2  11,15-ether intermediates, having pharmacological activity. Particularly, the compounds described herein are useful as platelet aggregation inhibitors. The present invention describes PGI 2  11,15-ether intermediates. These compounds are intermediates for preparing corresponding prostacylcin-type compounds with pharmacological utility, e.g., platelet aggregation inhibitors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending application Ser. No. 819,940, filed Jul. 28, 1977; which is a continuation-in-part of Ser. No. 725,550, filed Sept. 22, 1976, now abandoned; which was a continuation-in-part of Ser. No. 716,770, filed Aug. 23, 1976, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel compositions of matter which are derivatives of prostacyclin or PGI₂. The chemical name for prostacyclin is (5Z)--5,6--didehydro--9-deoxy--6,9.sup.α epoxy--PGF1.sup.α. Specifically the present invention relates to PGI₂ 11,15-ether intermediates.

Prostacyclin itself was first reported as "PGX" by Moncada and his co-workers. See Moncada, et al., Prostaglandins 12:658-713 (1976). Prostacyclin is a circulating hormone in the arterial circulation of mammals. See "Prostacyclin As A Circulating Hormone", Nature 273:767-768 (June 29, 1978) and Grycleweski, R. J. et al., "Generation of Prostacyclin By Lungs In Vivo And Its Release Into Arterial Circulation", Nature 273:765-767 (June 29, 1978).

PRIOR ART

Subsequent to any invention described herein the existence of prostacyclin as a naturally-occurring composition of matter was reported in the aforementioned references.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula ##STR1## or a mixture comprising that compound and the enantiomer thereof, wherein W₃ is α--OR₃₃ :β--H, α--H:β--OR₃₃, or α:CH₂ OR₃₃ :β--H, wherein R₃₃ is

(a) tetrahydropyranyl,

(b) tetrahydrofuranyl,

(c) a group of the formula --C(OR₁₄)(R₁₅)--CH(R₁₆)(R₁₇), wherein R₁₄ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₁₅ and R₁₆ are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2 or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R₁₅ and R₁₆ are taken together, --(CH₂)a-- or --(CH₂)b--O--(CH₂)c, wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R₁₇ is hydrogen or phenyl, or

(d) carboxyacyl including

(a')--CO--(Ph II), wherein (Ph II) is phenyl optionally substituted by one--5 is alkyl of one to 4 carbon atoms, inclusive, bromo, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, provided that not more than two such substituents are other than alkyl, and that the total number of carbon atoms, in the substituents does not exceed 10 carbon atoms,

(b') --CO--(Ph III), wherein (Ph III) is phenyl substituted by --COOR₃₀, wherein R₃₀ is alkyl of one to 4 carbon atoms, inclusive,

(c') --CO--(Np I), wherein (Np I) is naphthyl optionally substituted as is (Ph II)

(d') --CO--R₃₁, wherein R₃₁ is alkyl of one to 7 carbon atoms, inclusive,

wherein L is

(1) --(CH₂)_(d) --C(R₂)₂,

(2) --CH_(2--O--CH) ₂ --Y--, or

(3) --CH₂ CH═CH--,

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one of R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ --, or --(CH₂)₂,

wherein Q₂ is oxo, .sub.α --H:.sub.β --H, α--OR₃₃ :.sub.β --R₈, or .sub.α --R₈ :.sub.β --OR₃₃, wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and R₃₃ is as defined above,

wherein R₁ is

(1) --COOR₃,

(2) --CH₂ OH, (3) --CH₂ N(R₉)(R₁₈),

(4) --CO--N(R₉)(R₁₈) or

(5) tetrazolyl, wherein R₃ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive,

(g)--(p-Ph)--NH--CO--(p-Ph)--NH--CO--CH₃,

(h) --(p-Ph)--NH--CO--(Ph),

(i) --(p-Ph)--NH--CO--CH₃,

(j) --(p-Ph)--NH--CO--NH₂,

(k) --(p-Ph)--CH═N--NH--CO--NH₂,

(l) 2-naphthyl,

(m) CH(R₁₁)--CO--R₁₀, wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, wherein R₁₁ is hydrogen or benzoyl, (Ph) is phenyl and (p-Ph) is 1,4 -phenylene or

(n) a pharmacologically acceptable cation;

wherein R_(g) is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive,

wherein R₄ is

--C(R₅)(R₆)C_(g) H_(2g--CH) ₃,

--C(R₅)(R₆)--Z--(Ph I), or

--CH_(2--CH)═CH--CH₂ Ch₃,

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆₋₋ and (Ph I); wherein (Ph I) is phenyl optionally substituted by one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇₋₋ wherein R₇ is alkyl of one to 4 carbon atoms. inclusive, with the proviso that not more than two such substituents are other than alkyl and such substituents being either the same or different; and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof.

Compounds in accordance with the present invention are prepared by chemical methods and have pharmacological uses as chemical intermediates for preparing pharmacologically active substances as described in U.S. Pat. No. 4,158,667, issued June 19, 1979, incorporated here by reference and are hydrolyzed to corresponding C-11 and/or C-11,C-15 alcohols which are useful for a variety of pharmacological purposes. Accordingly, the hydrolyzed C-11 and/or C-11,C-15 alcohols are especially useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular drafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks and long-term prophylaxis following myocardial infarcts and strokes. For these purposes, the compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Dosages in the range about 0.01 to about 10 mg/kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The addition of these compounds to whole blood provides in vitro applications, such as storage of whole blood to be used in heart-lung machines. Additionally, whole blood containing these compounds can be circulated through limbs and organs, e.g., heart and kidneys, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. Blocking of aggregated platelets is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor person or animal, to the perfused whole body, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.0001-1.0 μg/ml of whole blood. These compounds are also useful in preparing platelet-rich concentrates from blood for use in treating thrombocytopenia or in chemotherapy. 

We claim:
 1. A compound of the formula ##STR2## or a mixture comprising that compound and the enantiomer thereof, wherein W₃ is α-OR₃₃ :β-H, α-H:β-OR₃₃, or α:CH₂ OR₃₃ :β-H, wherein R₃₃ is(a) tetrahydropyranyl, (b) tetrahydrofuranyl, (c) a group of the formula --C(OR₁₄)(R₁₅)--CH(R₁₆)(R₁₇), wherein R₁₄ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₁₅ and R₁₆ are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl or one to 4 carbon atoms, inclusive, or, when R₁₅ and R₁₆ are taken together, --(CH₂)a-- or --(CH₂)b--O--(CH₂)c, wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R₁₇ is hydrogen or phenyl, or (d) carboxyacyl including(a') --CO--(Ph II), wherein (Ph II) is phenyl optionally substituted by one-5 is alkyl of one to 4 carbon atoms, inclusive, bromo, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, provided that not more than two such substituents are other than alkyl, and that the total number of carbon atoms, in the substituents does not exceed 10 carbon atoms, (') --CO--(Ph III), wherein (Ph III) is phenyl substituted by --COOR₃₀, wherein R₃₀ is alkyl of one to 4 carbon atoms, inclusive, (c') --CO--(Np I), wherein (Np I) is naphthyl optionally substituted as is (Ph II) (d') --CO--R₃₁, wherein R₃₁ is alkyl of one to 7 carbon atoms, inclusive, wherein L is(1) --(CH₂)_(d--C)(R₂)₂ --, (2) --CH₂ --O--CH₂ --Y--, or (3) --CH₂ CH═CH--,wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one of R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ --, or --(CH₂)₂ --, wherein Q₂ is oxo, α-H:β-H, α-OR₃₃ :β-R₈, or α-R₈ :β-OR₃₃, wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and R₃₃ is as defined above. wherein R₁ is(1) --COOR₃, (2) --CH₂ OH, (3) --CH₂ N(R₉)(R₁₈), (4) --CO--N(R₉)(R₁₈ ) or (5) tetrazolyl, wherein R₃ is(a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, (g) --(p-Ph)--NH--CO--(p-Ph)--NH--CO--CH₃, (h) --(p-Ph)--NH--CO--(Ph), (i) --(p-Ph)--NH--CO--CH₃, (j) --(p-Ph)--NH--CO--NH₂, (k) --(p-Ph)--CH═N--NH--CO--NH₂, (l) 2-naphthyl, (m) CH(R₁₁)--CO--R₁₀, wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, wherein R₁₁ is hydrogen or benzoyl, (Ph) is phenyl and (p-Ph) is 1,4-phenylene or (n) a pharmacologically acceptable cation; wherein R₉ is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive, wherein R₄ is --C(R₅) (R₆)C_(g) H_(2g) --CH₃, --C (R₅) (R₆)--Z--(PH I), or --CH₂ --CH═CH--CH₂ CH₃,wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--0--); wherein Z represents an oxa atom (--0--) or C_(j) H_(2j) where in C_(j) H_(2j) is a valence bond or alkylene or one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ --and (Ph I); wherein (Ph I) is phenyl optionally substituted by one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl to one to 4 carbon atoms, inclusive, with the proviso that not more than two such substituents are other than alkyl and such substituents being either the same or different; and wherein X is (1) trans--CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --;including the lower alkanoates thereof. 